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The early invasive strategy with cardiac catheterization within 72 h of onset of symptoms has now become standard-of-care in the majority of countries around the world for patients with acute coronary syndromes (ACS). It is a Class 1B recommendation in the latest American College of Cardiology/American Heart Association practice guidelines for non–ST-segment elevation (NSTE) ACS and a Level 1A recommendation from the European Society of Cardiology (1,2). This very firm foundation of recommendation was established by several landmark studies carried out in the late 1990s and the early 2000s (3–6). In aggregate, these prospective randomized trials provided ample evidence that major cardiovascular endpoints such as death and myocardial infarction were reduced with an invasive strategy over a selective invasive strategy. The RITA-3 (Third Randomised Intervention Treatment of Angina) randomized trial provided a unique insight into this, because the trial also demonstrated reduced all-cause mortality at 5 years. Furthermore, when these trials were combined into a patient-level meta-analysis in patients who were risk stratified, it became apparent that this strategy was most beneficial in the high-risk patient cohorts, either defined by the GRACE (Global Registry of Acute Coronary Events) risk score or by other risk characteristics. The majority of the trials also have reported longer-term outcomes data, but none of them have reported beyond 5 years.

In this issue of the Journal, Henderson et al. (7) report on the long-term mortality outcomes of the RITA-3 trial at 10 years. This is a fascinating evaluation of long-term data that is so rarely possible, but it is facilitated by linking a national registry in the United Kingdom with a clinical trial cohort. The authors had previously reported the 5-year follow-up data from the RITA-3 trial (8). In the current report, the investigators use the office of national statistics to obtain all-cause mortality from 5 to 10 years following the original randomization. They find that the all-cause mortality reduction of 24% seen at 5 years has slowly dissipated by 10 years, with no statistical significance. The authors further stratify the results by the post-discharge GRACE score and find no clear treatment effect by low-, intermediate-, or high-risk categories. They also perform a multivariable model that identifies age, prior myocardial infarction or heart failure, and extent of coronary disease as important predictors of long-term mortality, but not the randomization strategy. Given these results, the authors conclude that we require further clinical trials of contemporary interventional strategies in patients with NSTE-ACS. These conclusions will likely give clinicians and guideline committees pause as they consider the current recommended strategies for management of patients with NSTE-ACS. To understand the results, we must consider both what we do know for certain from the RITA-3 investigators’ report and the limitations of the study.

What remain unknown are the long-term effects of a routine invasive strategy on recurrent ischemia, revascularization, and myocardial infarction. All of these endpoints were reduced at 5 years and remain important to patients and clinicians. This may in part be due to the fact that the mortality endpoint from 5 to 10 years is evaluated through a national database and not in the same fashion as during the trial. There is also no information on revascularization during follow-up beyond 5 years. However, through careful analysis, they have explored the rate of revascularizations up to 5 years and its potential effect on later mortality. These findings do not provide any further insight into why the mortality curves changed from 5 to 10 years of follow-up.

A consideration is that the treatment of patients with coronary artery disease is not static. Cardiologists sometimes quickly adapt new treatment strategies for perceived improvement in outcomes. One such example is the rapid uptake of drug-eluting stents in the early 2000s, which led to a quick adoption in a largely off-label population (9). This ongoing change in practice could also play a role in a cohort of patients who were managed by a selective invasive approach; because the information became known to the practicing community 5 years after the start of the trial, patients who were readmitted later after the initial completion of the trial may have been managed with a more invasive approach. However, a more conservative approach may have been selected for those who were already revascularized in the invasive arm (10). Unfortunately, the subsequent revascularization strategies beyond the 5-year time point in the RITA-3 trial are not known. The authors acknowledge this limitation; yet, the data are actually of some interest when the mortality curves are examined closely.

In the report, the authors have calculated the mortality rates (per 100 person-years) in the 2 treatment groups in 2-year intervals throughout the 10-year period. In the first 4 years of the trial, the investigators do not know the results of the 5-year mortality outcomes, but they become known later because of the publication showing a significant reduction in mortality after the initial 5 years of follow-up. In examining the mortality curves, some interesting features emerge. During the first 4 years, the annual mortality rate is 2.46 for the routine invasive strategy versus 3.38 for the selective invasive strategy. If one assumes that it took 1 to 2 years to disseminate the early trial results after the 5-year results, then examining the mortality rates at the tail end of the trial would be important because patients who were largely managed selectively invasively may have undergone more invasive treatment strategies for their recurrent ACS event. In this regard, the mortality rate per 100 person-years in the last 2 years of the trial for the selective invasive group is now substantially lower at 2.67 compared with the early part of the trial. This suggests that something changed in this cohort in the last 4 years of the 10-year follow-up period. However, the routine invasive strategy had event rates at 3.49/100 person-years, almost mimicking the event rate in the early phase of the selective invasive group. Patients who had already had their anatomy evaluated may in turn be managed with less revascularization (10). Although this remains speculation, it speaks to 2 issues: namely, relatively a lack of power to detect important mortality rates, but also an understanding that the follow-up treatment strategies are an important part of a trial and may affect subsequent outcomes.

So, what can the practicing physicians take from these findings? First are the possible explanations for observed long-term mortality in the RITA-3 trial. As noted, it is not clear if this loss of mortality reduction is due to attenuation of a direct treatment effect, treatment crossovers over the long-term follow-up, changing clinical therapeutics with improved antiplatelet and antithrombotic therapies, or simply the play of chance. Although each possibility may play a role, it seems most likely that the significant treatment effect from the initial study, the widespread clinical presentation of the trial findings, and guideline recommendations caused clinical practice to shift toward more routine invasive care. This is what we would hope happens with an active quality cycle in which findings are incorporated into clinical practice (11).

These findings of RITA-3 can therefore be interpreted as an important milestone of understanding the effect of an early invasive strategy on long-term outcomes. As such, the trial suggests that the benefit observed initially may not be translated into a longer benefit. How much of this attenuation can be ascribed to a change in practice pattern remains unclear. However, we should be heartened by the fact that physicians may be using the latest clinical trial data to improve the care for their patients with ACS, and therefore, our ability to interpret late outcomes may be heavily affected by the improving physicians’ performance around guidelines and the optimal care for patients with ACS. This is a very positive message indeed if you are a patient, but it makes it much harder if you are a researcher or guidelines writer in the field of cardiology.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Dr. Ohman has received research grants from Daiichi-Sankyo, Eli Lilly & Co., Gilead Sciences, and Janssen Pharmaceuticals; and has served as a consultant for Abiomed, AstraZeneca, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly & Co., Faculty Connection, Gilead Sciences, Janssen Pharmaceuticals, Merck, Stealth Peptides, The Medicines Company, and WebMD. Dr. Patel has reported that he has no relationships relevant to the contents of this paper to disclose.

American College of Cardiology Foundation

References

(2014) 2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol64:2645–2687.

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